Amino-lower-alkoxy-dibenzo [a, d] cyclohepten-5-ones and 10, 11-dihydro derivatives thereof



United States PatentO 3,350,405 AMINO LOWER ALKOXY DIBENZO[a,d]CYCLO-HEPTEN-S-ONES AND 10,11-DIHYDRO DERIVA- TIVES THEREOF John W.Schulenberg and Sydney Archer, Bethlehem, N.Y., assignors to SterlingDrug Inc., New York, N.Y., a corporation of Delaware No Drawing. FiledOct. 16, 1964, Ser. No. 404,506 12 Claims. ('Cl. 260294.7)

ABSTRACT OF THE DISCLOSURE This invention relates to tricycliccompounds, and in particular is concerned withdibenzo[a,d]cyclohepten-5-ones substituted on one of the benzene rings by an amino-lower-alkoxygrou and derivatives thereof.

The compounds of the invention have the following general formula:

wherein N=B is amino or substituted amino, X is ethylene or vinylene, Yis lower-alkylene and Z is carbonyl or divalent groups derived byconventional transformations of the carbonyl group.

In the above Formula I, N=B stands for an amino group which is basic andhas a molecular weight less than about 200. A basic radical is one ofthe aliphatic or araliphatic type that imparts to the molecules whichcontain it sufficient basicity (ionization to the extent of at least 10-so that the compounds readily form acidaddition salts with stronginorganic and organic acids. A particularly preferred group of aminoradicals include amino (NH lower-alkylamino, cycloalkylamino,(phenyl-lower-alkyl) amino, di-lower-alkylamino, dicycloalkylamino,N-(cycloalkyl)-lower-alkylamino, polymethylenimino of 5-7 ring members,4-morpholinyl, lpiperazinyl, 4-lower-alkyl 1 piperazinyl, 4-phenyl-1-piperazinyl, di-(phenyl-lower-alkyl)amino, and N-(phenyl lower alkyl)lower alkylamino. In the foregoing groups, lower-alkyl has from one tosix carbon atoms, and cycloalkyl has from five to six ring members,including cyclopentyl, cyclohexyl and lower-alkyl-substitutedcyclopentyl and cyclohexyl. Polymethylenimino of 5-7 ring membersincludes l-pyrrolidyl, l-piperidyl, 1- hexamethyleniminyl andlower-alkylated derivatives thereof.

In the above Formula I, X stands (CH CH or vinylene (CH=CH).

In the above Formula I, Y stands for a lower-alkylene bridge having itsconnecting valences on diiferent carbon atoms and contains at. least twoand not more than about five carbon atoms, thus including such radicalsas for ethylene and the like.

5 In the above Formula I, Z stands for the carbonyl group or divalentgroups derived therefrom. The latter include methylene (CH carbinol'[CH(OH)], loweralkylcarbinol [C (lower-alkyl) (OH)],phenyl-lower-alkylcarbinol [C (phenyl-lower-alkyl) (OH)],(hUower-alkylidene), C=(phenyl-lower-alkylidene), CH(lower-alkyl) and CH(phenyl-lower-alkyl). The lower-alkyl and loweralkylidene groups containfrom one to about six carbon atoms.

In the above Formula I, the side-chain OY-N=B can be in any position ofthe benzene ring, preferably in the 1-, 2-, or 3-positions. The benzenerings of the tricyclic system as well as any phenyl groups present inthe groups N=B and Z can bear additional substituents alkyl,lower-alkoxy, lower-alkylthio, lower-alkylsulfinyl andlower-alkylsulfonyl of one to six carbon atoms; halogen (includingfluorine, chlorine, bromine and iodine); trifluoromethyl, and the like.

The compounds of Formula I wherein X is CH CH and Z is 0:0 are preparedas follows:

cnlooon o \O NaOAc l OR OR t -Q CH CH 2 I 40 O 2H(Ni) c fl zsol) a 0R T\O polyphosl 0003 phone ac1d III IV /CH2GE{2 AlCh l},

V /CH2OE\[\; Hal Y-N=B W a l 9 r \0 ll VI CHzCH:

0--Y--N=B \C/ v I (X is Groom, z is co) Phthalic anhydride is condensedwith a lower-alkoxyphenylacetic acid (R is lower-alkyl of 1-6 carbonatoms) in the presence of anhydrous sodium acetate to give alower-alkoxybenzylidenephthalide (III). The latter hydrogenated in thepresence of Raney nickel is converted to a2-[Z-(lower-alkoxyphenyl)ethyl]benzoic acid (IV), which is then cyclizedin the presence of polyphosphoric acid or acetyl chloride and sulfuricacid to give a loweralkoxy-10,l l-dihydro-SH-dibenzo-[a,d]cyclohepten-5-one (V). The latter is dealkylated with anhydrousaluminum chloride to hydroxy-10,l l-dihydro-5H-dibenzo[a,d]cyclohepten-S-one (VI), which is then reacted with an aminoalkyl halide(HalY-N=B) in the presence of a strong base, such as an alkali metalalkoxide, hydride or amide, to produce anamino-lower-alkoxy-lO,ll-dihydro-SH-dibenzo[a,d]-cyclohepten-5-one (I; Xis CH CH Z is CO). The halogen (Hal) of the aminoalkyl halide can be anyof the halogens, chlorine, bromine and iodine. The compounds of FormulaI wherein X is CH=CH and Z is C=O are prepared as follows:

/CHGII\:

(1) NBS OAcyl (2) pyridine C II VII CH=CH H2O OAcyl --v C II 0 VIIICH=CH Hal-YN=B OH NaOMe C ll 0 1(Xis CH=CH, X is 00 An ester (VII) of ahydroxy-l0,ll-dihydro-SH-dibenzo- [a,d] cyclohepten-S-one (VI), such asthe acetate or other lower-alkanoate of 1-6 carbon atoms, when treatedwith N-bromosuccinimide in the presence of a catalyst such as benzoylperoxide, followed by treatment with pyridine, undergoes bromination anddehydrobromination to introduce unsaturation at the 10,11-position andproduce an acyloxy SH-dibenzo[a,d]cyclohepten-5-one (VIII). Alkalinehydrolysis of the latter gives ahydrOxy-SH-dibenzo[a,d]cyclohepten-5-one (IX) which is then etherifiedwith an aminoalkyl halide (Hal-YN=B) to give the desired aminoalkoxySH-dibenzo[a,d]cyclohepten-5-one (I; X is CH=CH, Z is CO).

The compounds of Formula I wherein Z stands for a divalent group otherthan carbonyl and derived therefrom are prepared as follows:

Z is CH by catalytic hydrogenation (palladium-oncharcoal) or byWolff-Kishner reduction (alkaline treatment of the hydrazone) ofcompounds where Z is CO.

Z is CH(OH): by lithium aluminum hydride reduction of compounds where Zis CO.

Z is C(lower-alkyl)OH or C(phenyl-lower-alkyl)OH: by reacting a compoundwhere Z is CO with a loWer-alkyl or phenyl-loWer-alkyl Grignard reagent.

Z is C: (lower-alkylidene) or C: (phenyl-lower-alkylidene): bydehydration, by means of acidic reagents, of

compounds where Z is C(lower-alkyl)OH or C(phenyllower-alkyl)OH,respectively.

Z is CH(lower-alkyl) or CH(phenyl-lower-alkyl): by catalytichydrogenation (palladium-on-charcoal) of compounds where Z is C:(lower-alkylidene) or C=(phenyllower-alkylidene), respectively.

The transformations of the carbonyl group can, of course, be carried outon intermediates, e.g., those of Formulas VI and IX, prior tointroducing the aminolower-alkyl side-chain.

When the radical -N=B in the above Formula I stands for an amino groupother than tertiary-amino, that is, when there is at least one hydrogenatom attached to the nitrogen, it is preferred to use alternative routesof synthesis. One of these routes comprises condensing a compound ofFormula VI or IX with an N-benzyl-N-(R)- amino-lower-alkyl halide,wherein R is lower-alkyl or cycloalkyl, in the presence of a strong basein the manner already described, and then subjecting the resulting N-benzyl N (R)-amino-lower-alkoxy compound to hydrogenolysis to remove thebenzyl group and thus produce a compound of Formula I wherein N=B isNH-R. A1- ternatively the N-benzyl group can be displaced by acarbethoxy group by reacting it with ethyl chloroformate and theresulting urethane cleaved by alkaline hydrolysis.

Still another way of introducing the amino-lower-alkoxy side-chaincomprises reacting a compound of Formula VI or IX with a lower-alkyleneoxide, thereby forming a compound with a hydroxy lower alkoxyside-chain, O-YOH, converting the latter to the p-toluenesulfonateester, and then reacting the latter with ammonia or the appropriateamine, HN=B.

When a compound of the invention is treated with an equivalent amount ofan inorganic or organic acid, it is converted to an acid-addition saltform. The salt form is the full equivalent of the free base insofar asthe inherent properties of the cationic moiety is concerned.Watersoluble salt forms derived from acids whose anions arepharmaceutically acceptable are of special interest for therapeutic use,but salt forms which are water-insoluble or contain toxic anions areuseful as characterizing derivatives of the free bases, or asintermediates in the purification of the free bases or in thepreparation of other salts by ion exchange reactions.

Pharmacological testing of compounds of Formula I has demonstrated thatthey are useful as antidepressant agents as evidenced by their abilityto prevent and reverse reserpine ptosis in mice and by the fact thatthey inhibit the enzyme phenylamine fi-hydroxylase in vitro.Anticonvulsant and psychomotor activity have also been found in thecompounds of the invention.

The structures of the compounds of the invention were established byelementary analyses, by the modes of preparation and by ultraviolet andinfrared spectra.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 (a) m-Anisylidenephthalide [111; OR is m-OCH A mixture of 99.5g. of m-methoxyphenylacetic acid, 78.9 g. of phthalic anhydride and 6 g.of anhydrous sodium acetate was heated gradually to 260 C. in a Woodsmetal bath over a period of forty minutes and held at this temperaturefor about seventy-five minutes while allowing the mixture to distill.The reaction mixture was cooled, 1000 ml. of ethanol was added, and thesolid product was collected by filtration and washed with hot ethanol.The product was recrystallized from ethanol to give 97.9 g. ofm-anisylidenephthalide in the form of yellow-tan needles, M.P. l20.5l22C. (uncorr.).

(b) 2-[2-(m-meth0xyphenyl)ethyl1benz0ic acid [IV; OR

is m-OCH A iriixture of 212.9 g. of m-anisylidenephthalide and 1600 ml.of absolute ethanol was hydrogenated in the presence of 200 g. of Raneynickel catalyst until two molar equivalents of hydrogen had beenabsorbed. The hydrogenation was complete in about three hours, and thecatalyst was removed by filtration. The filtrate was evaporated todryness and the residue was taken up in 1 liter of chloroform andstirred and heated with 60 g. of sodium bicarbonate in 3 liters ofwater. The aqueous solution was separated, filtered and acidified, andthe precipitated acid was collected, washed with water and dried fortwenty-four hours at 6070 C. over phosphorus pentoxide to give 83.3 g.of 2-[2-(m-methoxyphenyl) ethyl]benzoic acid, M.P. 116.8-119 C.(uncorr.).

(c) 2 methoxy 10,11 afihydro-5H-dibenzo[a,d]cyclo hepten-S-one [V; OR is2-OCH 2-[2-(m-methoxyphenyDethyl]benzoic acid (10.25 g.) and 100 ml. ofacetyl chloride were stirred and warmed until solution was complete.Sulfuric acid (0.5 ml.) was added, followed by stirring while allowingthe excess acetyl chloride to boil 011 over a period of forty minutes.The resulting orange solution was poured into 400 ml. of water and thesolid product was collected by filtration. The product wasrecrystallized from aqueous ethanol and dried over phosphorus pentoxidefor sixty hours to give 7.4 g. of2-methoxy-10,l1-dihydro-5H-dibenzo[a,d]cyclohepten-S-one in the form ofcolorless needles, M.P. 71.2- 73.5 C. (uncorr.); ultraviolet maxima at238 and 300 m (6:9,300' and 14,300), infrared absorption at 6.18, 6.2.9and 6.37

(d) 2 hydroxy 10,11 dihydr-5H-dibenz0[a,d]cyclohepten--0ne [VI; Z-OH] Amixture of 11.94 g. of 2-methoxy-l0,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one, 20.0 g. of anhydrous aluminum chlorideand 250 ml. of toluene was stirred under reflux for one andthree-quarter hours. The excess aluminum chloride was decomposed byaddition of ice water, and the solid product was collected by filtrationand Washed with Water. The benzene layer was concentrated to dryness andthe residue combined with the filtered solid product. The combinedproduct was suspended in methanol and the suspension filtered andconcentrated to dryness. The latter residue was suspended in 5% sodiumhydroxide solution, filtered, and the filtrate made acid with aceticacid. The precipitated product was collected, suspended in methanol andthe insoluble material removed by filtration. The filtrate wasconcentrated.

to a volume of less than 500 ml. and water was added to the point ofturbidity. The solution was chilled and the product collected to give11.06 g. of 2-hydroxy-10,1ldihydro-SH-dibenzo[a,d]cyclohepten-5-one inthe form of yellow plates, M.P. 141.4-143.8 C. (corn) whenrecrystallized from aqueous methanol.

2 acetoxy-10,11'-dihydro-5H-dibenzo[a,d]cyclohepten- 5-one was preparedby treating Zhydroxy-ltkll-dihydro-5H-dibenzo[a,d]cyclohepten-S-one withan excess of acetic anhydride in pyridine solution, and was obtained inthe form of colorless plates, M.P. 64-65 C. (uncorr.).

EXAMPLE 2 "(0) 3 methoxy 10,11 dihydr0-5H-dibenz0[a,d]cyclohepten-S-one[V; OR is 3-OCH A mixture of 10.25 g. of 2-[2-(p-methoxyphenyl)ethyl]benzoic acid and 75 ml. of polyphosphoric acid was stirred andheated at C. for five hours. The reaction mixture was added to 800 ml.of water, extracted with chloroform, and the chloroform extracts washedwith water, saturated sodium chloride solution, and filtered. Excessdilute sodium carbonate solution (300 ml.) was added, and the mixturestirred and warmed to evaporate the chloroform. The resulting suspensionwas extracted with ether and with chloroform, and the organic extractswere washed with water, saturated sodium chloride, dried andconcentrated to give 8.63 g. of 3- methoxy 10,11 dihydro-5H-dibenzo[a,d]cyclohepten-S- one which was used in the following procedure withoutfurther purification.

(d) 3 hydroxy 10,1I-dihydr0-5H-dibenz0 [a,d] cyclohepten-5-0ne [VI;3-OH] was prepared from 2.88 g. of 3 methoxy10,1l-dihydro-SH-dibenzo[a,d] cyclohepten- S-one and 5.0 g. of aluminumchloride according to the procedure described above in Example 1, part(d). The product was recrystallized from methanol to obtain 3- hydroxy10,11 dihydro-SH-dibenzo[a,dJcyclohepten-S- one in the form of light tanplatelets, M.P. l46-147.2 C. (uncorr.).

By replacing the m-methoxyphenylacetic acid in Example 1 by a molarequivalent amount of O-methoxyphenylacetic acid and carrying it throughthe succeeding transformations, there can be obtained 1-hydr-oxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-S-one [VI; 1-OH].

By replacing the phthalic anhydride in Example 1 by a molar equivalentamount of 3,4-dimethoxyphthalic anhydride or 3,4-dimethylphthalicanhydride there can be obtained, respectively,2-hydroxy-7,S-dimethoxy-IO,1l-dihydro 5H-dibenzo[a,d]cyclohepten-S-oneor 2-hydroxy- 7,8 dimethyl 10,11 dihydro5H-dibenzo[a,d]cyclohepten-5-one.

EXAMPLE 3 (a) 2-acet0xy-5H-dibenz0[a,d]cyclohepten-5-0ne [VIII;

OAcyl is 2-OCOCH A mixture of 2.66 g. of 2-acetoxy-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one [Example 1, part (d-)], 2.14 g. ofN-bromosuccinimide, 0.11 g. of benzoyl peroxide and 50 ml. of carbontetrachloride Was stirred at reflux for one and one-half hours. Thereaction mixture was filtered into 50 ml. of pyridine and allowed tostand at room temperature for three days. The mixture was thenheatedwhile distilling off the carbon tetrachloride and pyridine over aperiod of five hours. The residue was added to water, the product wascollected, Washed with water, dried and recrystallized from petroleumether (Skellysolve C) to give 1.57 g. of 2-acetoxy-5H-dibenzo [a,d]cyclohepten-S-one in the form of pale yellow plates, M.P. 102.5105.5 C.(uncorr.).

A mixture of 1.53 g. of 2-acetoxy-5H-dibenzo [a,d] cyclohepten-S-one and50 ml. of 5% aqueous sodium hydroxide was allowed to stand at roomtemperature overnight, and then was stirred for one hour and filtered.The filtrate was saturated with carbon dioxide and the precipitatedproduct was collected and recrystallized from aqueous methanol to give1.18 g. of 2-hydroxy-5H-dibenzo[a,d]cyclohepten-S-one as a light tansolid, M.P. -198 C. (uncorr.); ultraviolet maxima at 226, 249, 279 and350 mu (e=13,500, 22,900, 36,100 and 3,350), infrared absorption at6.25, 6.40, 6.49 and 7.02

By replacing the 2-acetoxy-10,1l-dihydro-SH-dibenzo-[a,d]cyclohepten-5-one in Example 3, (a) by a molar equivalent amount ofthe acetates of 3-hydroxy-10, 1 1-dihydro-5 H-dibenzo [a,d] cyclohepten-5-one, 1-hydroxy-10,1 l-dihydro-SH-dibenzo [a,d] cyclohepten- 5-one,

2-hydroxy-7,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d]

cyclohepten-S-one or2-hydroxy-7,8-dimethyl-10,1l-dihydro-SH-dibenzo[a,d]-

cyclohepten-S-one there can be obtained, respectively,3-hydroxy-5H-dibenz0 a,d] eyclohepten-S-one, l-hydroxy-S H-dibenzo [a,d]cyclohepten-S-one, 2-hydr0xy-7, 8-dimethoxy-5H-dibenzo [a,d]cyclohepten- -one or 2-hydroxy-7,S-dirnethyl-SH-dibenzo [a,d]cyclohepten- 5 -one.

EXAMPLE 4 Z-hydroxy-I 0,1 1 -dihydro-5H-dibenz0[a,d 1 cycloheptene Asolution of 5.84 g. of 2-hydroxy-10,ll-dihydro-SH-dibenzo[a,d]cyclohepten-S-one [Example 1, part (d)] in 200 ml. of aceticacid was hydrogenated in the presence of 1.74 g. ofpalladium-on-charcoal catalyst. The hydrogenation was complete insixteen hours, the catalyst was removed by filtration and the filtrateconcentrated to dryness. The residue was dissolved in dilute aqueoussodium hydroxide, the solution filtered and saturated with carbondioxide. The product was collected, dried and recrystallized frombenzene to give 4.54 g. of 2-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in the form of light tanplatelets, M.P. 164.5l67 C. (uncorn).

By replacing the 2-hydroxy-l0,1l-dihydro-SH-dibenzo-[a,dlcyclohepten-S-one in the foregoing preparation by a molarequivalent amount of 3-hydroxy-10,1Ldihydro-SH-dibenzo[a,dlcyclohepten-5-one,

1-hydroxy-10, 1 l-dihydro-5H-dibenzo [a,d1cyclohepten- 5 -one,

2-hydroxy-7,8-dimethoxy-10,1Ldihydro-SH-dibenzo- [a,dlcyclohepten-S-oneor 2-hydroxy-7,8-dimethyl-l 0,1 1-dihydro-5H-dibenzo[a,d] cyclohepten-S-one there can be obtained, respectively,

3-hydroxy-10,l1-dihydro-5H-dibenzo[a,d]cycloheptene,

1-hydroxy-l0,1l-dihydro-SH-dibenzo[a,dlcycloheptene,

2-hydroxy-7,S-dimethoxy-10,1l-dihydro-5H-dibenzo- [a,d] cycloheptene, or

8 2-hydroxy-7,S-dimethyl-l0,1l-dihydro-SH-dibnzo[a,dl-

cycloheptene.

EXAMPLE 5 2 (Z-diethylaminoefhoxy) 10,1I-dihydro-SH-dibenzo- [a,d]cycl0hepten-5-0ne [1; X is CH CH Y is CH CH Z is co, N:B is N(C H2-hydroxy-10,1l-dihydro-SH-dibenzo[a,d,]cyclohepten- 5-one (8.38 g.)(Example 1) and 2.52 g. of sodium methoxide were suspended in 300 ml. ofchlorobenzene. The mixture was distilled until the head temperaturereached 132 C. The suspension was cooled and 6.34 g. of2-diethylaminoethyl chloride was added. The reaction mixture was stirredunder reflux for two and one-half hours. There was then added 40 ml. of35% aqueous sodium hydroxide, the layers were separated and the sodiumhydroxide solution washed with chloroform. The combined organic extractswere washed three times with water and twice with saturated sodiumchloride solution and dried over anhydrous magnesium sulfate. Thesolvents were evaporated, the residue dissolved in 200-250 ml. of etherand an excess of ethereal hydrogen chloride was added. The hydrochloridesalt which separated was collected and recrystallized from an isopropylalcohol-ether mixture to give 9.10 g. of2-(2-diethylaminoethoxy)-10,1l-dihydro- 5H-dibenzo[a,d]cyclohepten-S-onein the form of its hydrochloride salt, pale yellow needles, M.P.118.6-120.4 C. (corr.).

2 (2 diethylaminoethoxy) 10,11 dihydro 5H dibenzo[a,d]cyclohepten-S-onewas found to be active in reversing ptosis at mg./ kg. when injectedintraperitoneally to mice medicated with 2 mg./kg. of reserpine; and wasfound to be 204% as active as imipramine in inhibition of phenylaminefl-hydroxylase in vitro.

The examples in the following table were prepared according to theprocedure described in Example 5, using the appropriate startingmaterial of Examples 14 and the appropriate aminoalkyl halide. Thecompounds of the table have antidepressant activities similar to thoseof the compound of Example 5.

Example X z Y-N=B i s itii io r'r'. C Chain HCl alt 6 CH=CH C=O CHzCHzN(C2Ha)r 2 140. 8-142. 2 7 CH=CH C=O CHQCHZCHQN(CHQ)1 2 193. 2-193. 8 8CH=CH C=O CH2CH2N(CH3)I 2 183. 8-186. 0 9 CHaCHa C=O CHzCHaCHzN (CH3): 2193. 6-194. 3 10 CHICH: C=O CH:CHgN(CHa)z Z 211. 2-212. 8 11 CHzCHz C=OCH2CH2N(CH:)(CH1CaHs) 2 165. 8-175. 0 12 CH=CH =0 CHnCH2N(CHa) (CHQCQHB)2 199. 2-200. 8

CHQCH! 13 CH=CH C=O CHzCHzN 2 182. 8484.2

C H OHa C HzC H:

14 CHzCHa C=O CHzCHzN 2 201. 0202.0

CHgCHz C HaCH:

15 CH=CH o=o or'nonm on, 2 199.2-20o.e

C HzCH:

C HzC H! 16 CHa CHz C=O CHgCHaN CH: 2 171. 2-173. 8

CHzCHz 17 CHgCHn C=O CHzCHzIKCHs), 3 168. 6470.6 18 CHgCHl CH: CHiCHzN(011a): 2 173. 0475.0

EXAMPLE 23 (p chlorobenzyl) 2 (2 diethylaminoethoxy)-5- hydroxy 5Hdibenzo [a,d]cycloheptene [1; X is CH CH, Y is CH CH Z is C(OH)(CH CH,,Cl-4), N=B is N(C H was prepared from 4.18 g. of 2-(2-diethylaminoethoxy) -5H-dibenzo-[a,d] cyclohepten-S one (Example 6) andthe Grignard reagent from 0.66 g. of magnesium and 4.19 g. ofp-chlorobenzyl chloride. The product was chromatographed on silica gel,eluted with ether and then recrystallized from hexane to giveS-(pchlorobenzyl) -2-(Z-dicthylaminoethoxy)-5-hydroxy 5H-dibenzo[a,d]cycloheptene, MJP. 83-88 C. (uncorr.).

By replacing the benzyl chloride in Example 19 by a molar equivalentamount of n-hexyl bromide or 2-phenylethyl bromide there can beobtained, respectively,5-(nhexyl)-2-(Z-diethylaminoethoxy)-10,11-dihydro 5hydroxy-5H-dibenzo[a,d]cycloheptene or 5-(2-phenylethyl)2-(2-diethylaminoethoxy)-10,11-dihydro-5-hydroxy 5H- dibenzo [a,d]cycloheptene.

By replacing theZ-(Z-diethylaminoethoxy)-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5-onein Example 19 by a molar equivalent amount of Z-[Z-(N-benzyl-N-methylamino)ethoxy]-10,ll-dihydro 5H dibenzo[a,d] cyclohepten-S-one,2-[2-(1 pyrrolidyl)ethoxy] 5H dibenzo[a,d]cyclohepten-5-one, 2[2-(1-piperidyl)ethoxy]- 5 H-dibenzo [a,d1 cyclohepten-S-one, 3-(Z-dimethylaminoethoxy) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-5- one,1 (2 diethylaminoethoxy)-5H-dibenzo[a,d]cyclohepten 5 one, or 2 (2diethylaminoethoxy)-7,8-dimethoxy 10,11 dihydro-5H-dibenzo[a,d]cyclohepten-S- one, there can be obtained, respectively, 5-benzyl-2-[2-(N-benzyl-N-methylamino)ethoxy] 10,11 dihydro-5- hydroxy 5Hdibenzo[a,d1cycloheptene, 5 benzyl 2- [2 -(1 pyrrolidyl)ethoxy] 5hydroxy 5H dibenzo [a,d]cycloheptene, 5 benzyl 2 [2 (1 piperidyl)ethoxy] 5 hydroxy 5H dibenzo[a,d1cycloheptene, 5 benzyl 3 (2dimethylaminoethoxy) 10,11-dihydro 5 hydroxy 5Hdibenzo[a,d]cycloheptene, 5- benzyl l (2 diethylaminoethoxy) 5 hydroxy5H- dibenzo[a,d]cycloheptene, or 5 benzyl 2 (2 diethylaminoethoxy) 7,8dimethoxy 10,11 dihydro 5 hydroxy-SH-dibenzo [a,d] cycloheptene.

EXAMPLE 24 2 (2 dimethylaminoethoxy) 5 methylene 10,11-

dihydro-5H-dibenzo]a,d]cycl0heptene [1; X is CH CH Y is CH CH Z is (rCH2, 'iS

2 (2 dimethylaminoethoxy) 10,11-dihydro 5 hydroxy 5 methyl 5Hdibenzo[a,d] cycloheptene (4.63 g.) (Example 21) was dissolved in 300ml. of benzene and 200 ml. of chloroform. To this solution was added 20ml. of a saturated solution of hydrogen chloride in ether and themixture was allowed to stand for twentyfour hours. The solvents weredistilled off slowly, the residual suspension diluted with dry ether andthe product collected and recrystallized from chloroform-benzene to give3.80 g. of 2-(Z-dimethylaminoethoxy)-5-methylene-10,1l-dihydro-5H-dibenzo[a,d]cycloheptene in the form of itshydrochloride salt, M.P. 188189 C. (corn).

By replacing the 2-(Z-dimethylaminoethoxy)-l0,1l-dihydro5-hydroxy-S-methyl-SH-dibenzo[a,d] cycloheptene in Example 24 by a molarequivalent amount of S-benzyl-2-(2-diethylaminoethoxy)-10,11-dihydro-5-hydroxy 5H-dibenzo[a,d]cycloheptene, 5 (p-chlorobenzyl)-2-(2-diethylaminoethoxy) 5hydroxy 5H dibenzo[a,d]cycloheptene, 5 (n hexy) 2 (2 diethylaminoethoxy)10,11 dihydro 5 hydroxy SH dibenzo[a,d]cyclo- 12 heptene, or 5 (2phenylethyl) 2 (2 diethylaminoethoxy) 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene, there can be obtained, respectively, 2- (2diethylaminoethoxy) 5 benzylidene 10,11 dihydro 5Hdibenzo[a,d]cycloheptene, 2 (2 diethylaminoethoxy) 5 (pchlorobenzylidene) 5H dibenzo [a,d]cycloheptene, 2 (2diethylaminoethoxy) 5 (nhexylidene) 10,11 dihydro 5Hdibenzo[a,d]cycloheptene, or 2 (2 diethylaminoethoxy) 5 (2phenylethylidene) 10,11 dihydro 5H dibenzo[a,d]cycloheptene.

EXAMPLE 25 2 (2 dimethylaminoethoxy) 10,11 dihydro 5-methyl-SH-dibenzo[a,d]cycl0heptene [1; X is CH CH Y is CH CH Z is CHCH NB is N(CH A solution of 2.05 g. of 2-(2-dimethylaminoethoxy)-5-methylene 10,11 dihydro 5H dibenzo[a,d]cycloheptene in the form of itshydrochloride salt (Example 24) in 200ml. of ethanol was hydrogenated atroom temperature in the presence of 0.25 g. of palladium-on-charcoalcatalyst. After two and one-quarter hours the requisite mole-equivalentof hydrogen had been absorbed, and the mixture was filtered andconcentrated to dryness. The residue was recrystallized from achloroform-benzene mixture to give 2.01 g. of 2-(2-dimethy1aminoethoxy)10,11-dihydro 5 methyl-SH-dibenzo[a,d]cycloheptene in the form of itshydrochloride salt, M.P. 146.8-1520" C. (corn).

2 (2 dimethylaminoethoxy) 10,11 dihydro 5-methyl-5H-dibenzo[-a,d]cycloheptene was found to be active at 30 mg./kg.in reversing reserpine ptosis in mice.

By replacing the 2 (2 dimethylaminoethoxy) 5- methylene 10,11 dihydro 5Hdibenzo[a,d]cycloheptene in Example 25 by a molar equivalent amount of 2(2 diethylaminoethoxy) 5 benzylidene 10,11- dihydro 5H dibenz0[a,d]cycloheptene, 2 (2 diethylaminoethoxy) 5 (p chlorobenzylidene) 5Hdibenzo [a,d]cycloheptene, 2 (2 diethylaminoethoxy) 5 (n hexylidene)10,11 dihydro 5H dibenzo[a,d]cycloheptene, or 2 (2 diethylaminoethoxy) 5(2 phenylethylidene) 10,11 dihydro 5H dibenzo[a,d]cycloheptene, therecan be obtained, respectively, 2-(2-diethylaminoethoxy) 5 benzyl 10,11dihydro 5H dibenzo[a,d]cycloheptene, 2 (2 diethylaminoethoxy)-5- (pchlorobenzyl) 5H dibenzo[a,d] cycloheptene, 2- (2 diethylaminoethoxy) 5(n hexyl) 10,11 dihydro 5H dibenzo[a,d1cycloheptene, or 2 (2diethylaminoethoxy) 5 (2 phenylethyl) 10,11 dihydro-SH-dibenzo[a,d]cycloheptene.

EXAMPLE 26 2 (2 dimethylaminoethoxy) 10,11 dihydro 5hydroxy-SH-dibenzo]a,d]cycl0heptene [1; X is CH CH Y is CH CH Z is CHOH,N B is N(CH 2 (2- dimethylaminoethoxy) 10,11 dihydro 5H-dibenzo[a,d]cyclohepten 5 one (from 3.98 g. of its hydrochloride salt)(Example 10), was dissolved in ml. of tetrahydrofuran, 0.91 g. oflithium aluminum hydride was added, and he mixture was stirred for sixhours. The reaction mixture was filtered, the solid material slurriedwith hot chloroform, and the tetrahydro- *fu-ran and chloroform solutionwere combined and concentrated to dryness. The residue was crystallizedfrom 40 ml. of ether to give 2.77 g. of2-(2-dirnethylaminoethoxy)-10,11-dihydro 5 hydroxy 5H dibenzo[a,d1cycloheptene, M.P. 100.8-103.2 C. (corr.).

EXAMPLE 27 Z-(Z-methylaminoethoxy) 10,11 dihydro-5H dibenzo [a,d]cyclohepten-S-one [I; X is CH CH Y is CH CH Z is CO, N==B is NHCH 2-[Z-N-benzyl-N-methylamino ethoxy] 10,11-dihydro5H-dibenzo[a,d]cyclohepten-S-one (7.39 g. of the hydrochloride salt)(Example 11) in 200 ml. of ethanol was hydrogenated at room temperaturefor two and one-half hours in the presence of 0.74 g. ofpalladium-on-charcoal catalyst. The

droxylase.

EXAMPLE 28 (a) 2-[2-(N carbethoxy-N-methylamino)ethoxy]-5H- dibenz[a,d]cyclohepten-S-one A benzene solution of 2-[2-(N benzyl Nmethylamino)ethoxy]-SH-dibenzo[a,dJcyclohepten-S-one (from 10.15 g. ofits hydrochloride salt) (Example 12) was treated with 3.0 ml. of ethylchloroformate. The reaction mixture was allowed to stand overnight andthen refluxed for twenty-four hours. The solvents were removed in vacuoand the residue dissolved in ether and treated with an excess ofhydrogen chloride in ethanol. The solid product was filtered, Thefiltrate was concentrated and the residue Was recrystallized fromn-hexane to give 8.21 g, of 2-[2-(N-oarbethoxy N methylamino)ethoxy]SH-dibenzo[a,dJcyclohepten-S-one, M.P. 7576 C. (uncorn); infraredabsorption at 3.37, 5,92, 6.15, 6.25, 6.71 and 6.75-6.85n.

(b) 2-(2-methylaminoethoxy) H dibenzo[a,d]cycl0- hepten-S-one [I; X isCH CH, Y is CH CH Z is CO, N =B is NHCH A mixture of 7.58 g. of2-[2-(N-carbethoxy-N-methylamino)eth0xy]-5Hdibenzo[a,d]cyclohepten-5-one and 7.05 g. of potassium hydroxide in 75ml. of ethanol was refluxed for five and one-half hours. The reactionmixture than half its volume, 250 ml. of water was added and the mixtureextracted with ether.

recrystallized from n-hexane to give2-(2-methylaminoethoxy)-5H-dibenzo[a,d,]cyclohepten-5-one, M.P. 81.2-84.0 C. (corn). A sample of the hydrochloride salt when recrystallizedfrom isopropyl alcohol had the M.P. 217.5- 221 C. (uncorn).

EXAMPLE 29 (a) Z-(Z-hydroxyethoxy) 10,11 dihydro 5H-dizenzo [a,d]cyclohepten-5-one Eethylene oxide (2 ml.) was added to a solution of6.73 g. of 2-hydroxy-10,11 dihydro-5H-dibenzo[a,d]cyclohepten-S-one and2.45 g. of sodium hydroxide in 25- 30 ml, of water held at 5 C. Thereaction mixture was stirred at 05 C. for two hours and then for twohours while allowing the solution to warm to room temperature. Themixture was stirred for two hours longer and acidified with hydrochloricacid. The solid material was separated, taken up in chloroform, andstirred and heated with excess sodium carbonate solution. The baseinsoluble material comprising 2-(2-hydroxyethoxy)-10,1l-dihydro-5H-dibenzo[a,d]cyclohepten-S-one was isolated and used directly in thenext reaction.

(b) p-Toluenesulfonate ester of 2-(2-hydroxyethoxy)-IO,

11-dihydr0-5H-dibenz0[a,d] cycloheplen-S-one The crude2-(2-hydroxyethoxy)-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one frompart (a) (5.04 g.) was dissolved in 25 ml. of pyridine. The solution wascooled to 4-6 C. and 3.93 g. of p-toluenesulfonyl chloride in 5 ml. ofpyridine was added over a period of fourteen minutes. The reactionmixture was stirred at 5-10" C. for two and one-half hours, allowed tostand overnight and then stirred at 20-25 C. for two and one-half hours.The reaction mixture was added to ice-water containing ml. ofconcentrated hydrochloric acid and extracted with benzene. The benzeneextracts were washed with water and sodium chloride solution, dried overanhydrous magnesium sulfate and concentrated. The residual 6.25 g. ofoil comprising p-toluenesulfonate ester of2-(2-hydroxyethoxy)-10,11-dihydro 5H dibenzo[a,d]cyclohepten-5- one wasused directly in the next reaction.

(c) 2-( 2-ethylaminoethoxy) 10,11 dihydro-.iH-dibnzo [a,d]cyclohepten-S-one [I; X is CH CH Y is CH CH Z is CO, N=B is NHC H Amixture of 5.25 g. of the p-toluenesulfonate ester of2-(2-hydroxyethoxy) 10,11 dihydro-5H-dibenzo[a,d] cyclohepten-S-one, 4ml. of anhydrous ethylamine and 50 ml. of toluene was stirred withcooling for two hours, allowed to stand overnight at room temperatureand then stirred with gentle reflux for eight hours. The product wasisolated, dissolved in ether and treated with an eX- cess of hydrogenchloride in ethanol. The resulting product was recrystallized fromisopropyl alcohol to give 2-(2- ethylaminoethoxy) 10,11dihydro-SH-dibenzo[a,d]cyclohepten-S-one in the form of itshydrochloride salt, M.P. 186.0191.0 C. (corn).

By replacing the ethylamine in the foregoing procedure by a molarequivalent amount of ammonia, cyclohexylamine, cyclopentylamine,4-methylcyclohexylamine or 2- phenylethylamine, there can be obtained,respectively, 2- (2-aminoethoxy)-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-S-one, 2-(2-cyclohexylaminoethoxy) 10,11 5H-dibenzo[a,d]cyclohepten 5-one, 2-(2-cyclopentylaminoethoxy) 10,11dihydro-SH-dibenzo[a,dJcyclohepten-S- one,2-[2-(4-methylcyclohexylamino) ethoxy] 10,11 dihydro 5Hdibeuzo[a,dJcyclohepten-S-one, or 2-[2-(2- phenylethylamino)ethoxy]10,11 dihydro-SH-dibenzo [a,d] cyclohepten-S-one.

We claim:

1. A compound of the formula 2. A compound of the formula 2% wherein Yis a lower-alkylene bridge having its connecting valences on difiYerentcarbon atoms, and N=B is dilower-alkylamino.

wherein 3. A compound of the formula wherein Y is a lower-alkylenebridge having its connecting valences on different carbon atoms, and N Bis dilower-alkylamino.

4. 2-[2-(N-benzy1 N methy1amino)ethoxy] 10,11-dihydro-SH-dibenzo[a,d]cyclohepten-S-one.

5. 2[2-(N-benzy1 N methylamino)ethoxy] benzo[a,d]cyclohepten-S-one.

6, 2-[2-(l-pyrrolidyDethoxy] 5H dizenzo[a,d]cyclohepten-S-one.

7 2-[2-(l-pyrrolidyDethoxy] 10,11dihydro-SH-dibenzo[a,d]cyc1ohepten-S-one.

SH-dihepten-S-one.

9. 2-[2-(l-piperidyDethoxy] 10,11 dihydro SH-di- References Cited UNITEDSTATES PATENTS 15 2,461,038 2/1949 Cusic 260570.7 2,556,102 6/1951 Olinet a1 260294.7 3,227,716 1/1966 Harms 260-294.7

WALTER A. MODANOE, Primary Examiner.

20 A. D. SPEVACK, Assistant Examiner. I

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,350,405 October 31, 1967 John W. Schulenberg et :11.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 3, line 48, "X is CO" should read Z is CO Column 7, line 1,"7,8dimethyl-" should read -7,8-dimethoxy-'--. Column 13, line 55,"dizenzo" should read dibenzo Column 14, line 36, "-l0,1l-5H-" shouldread -10,l1-dihydro':'-5H- Column 15, line 17, "dizenzo" should readdibenzo Signed and sealed this 16th day of September 1969.

(SEAL) Attest:

Edward M. Fletcher, Jr. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

1. A COMPOUND OF THE FORMULA